Essential role of Ret for defining non-peptidergic nociceptor phenotypes and functions in the adult mouse

Abstract

Transduction of pain following noxious stimuli is mediated by the activation of specialized ion channels and receptors expressed by nociceptive sensory neurons. A common early nociceptive sublineage expressing the nerve growth factor receptor TrkA diversifies into peptidergic and non-peptidergic nociceptors around birth. In this process, peptidergic neurons maintain TrkA expression, while non-peptidergic neurons downregulate TrkA and upregulate the common glial-derived neurotrophic factor family ligand receptor Ret and bind the isolectin B4 (IB4). Although Ret can have profound impacts on the molecular and physiological properties of nociceptive neurons, its role is not fully understood. Here we have deleted Ret in small- and medium-size sensory neurons, bypassing the early lethality of the full Ret knockout. We identify that Ret is expressed in two distinct populations of small-medium sized non-peptidergic neurons, an IB4(+) and an IB4(-) population. In these neurons, Ret is a critical regulator of several ion channels and receptors, including Nav1.8, Nav1.9, ASIC2a, P2X3, TrpC3, TrpM8, TrpA1, delta opioid receptor, MrgD, MrgA1 and MrgB4. Ret-deficient mice fail to respond to mustard oil-induced neurogenic inflammation, have elevated basal responses and a failure to terminate injury-induced sensitization to cold stimuli, hypersensitivity to basal but not injury-induced mechanical stimuli, while heat sensation is largely intact. We propose that elevated pain responses could be contributed by GPR35, which is dysregulated in adult Ret-deficient mice. Our results show that Ret is critical for expression of several molecular substrates participating in the detection and transduction of sensory stimuli, resulting in altered physiology following Ret deficiency.

Deletion of Interleukin-6 Signal Transducer gp130 in Small Sensory Neurons Attenuates Mechanonociception and Down-Regulates TRPA1 Expression

“…3B). This suggests that gp130 deletion specifically targets Trpa1 expression, whereas expression of other ion channels of the TRP family, which substantially contribute to hypernociception in mouse models of pathological pain, is not regulated by gp130 (for review, see Dubin and Patapoutian, 2010 …”

“…Differential expression and sensitization of these putative ion channels very likely contribute to the mechanical hypersensitivity associated with chronic pain states. Despite the anticipated importance of such channels, the cellular and molecular mechanisms of mechanonociception are still incompletely understood (Lumpkin and Caterina, 2007;Dubin and Patapoutian, 2010;Delmas and Coste, 2013).…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…The transcription factors Runx1 and tlx3 are essential for the development of this class of neurons and directly regulate the expression of mMrgprD and mMrgprX1 starting around embryonic day 16 (Chen et al, 2006;Luo et al, 2007;Liu et al, 2008;Lopes et al, 2012;Xu et al, 2013). Runx1 also induces c-Ret in some neurons, which, in turn, switch on the expression of mMrgprA1, mMrgprA3, and mMrgprB4 in this subset of cells (Luo et al, 2007;Franck et al, 2011). After birth, Runx1 becomes a repressor of mMrgprAs, mMrgprB4, and mMrgprX1 and is turned off in this cell lineage, although it remains expressed in the mMrgprD subclass of neurons where it consequently leads to the exclusive expression of mMrgprD .…”

The emerging pharmacology and function of GPR35 in the nervous system

“…This is a strong example of employing the breadth of available GPR35 pharmacology to 389 build an argument for the direct contribution of this receptor (Alkondon et al, 2015). mice, leading to the observed behaviours (Franck et al, 2011). 426 GPR35 has also been observed in a subpopulation of small-to-medium diameter sensory 427 neurones that contained TRPV1 (transient receptor potential cation channel subfamily V member 1) 428 and larger sized neurones that convey non-nociceptive information (such as touch and light pressure), 429 which contained GPR35 but not TRPV1 (Ohshiro et al, 2008).…”